Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/50—Pyridazines; Hydrogenated pyridazines
  • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0048—Eye, e.g. artificial tears
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• the present invention relates to N- [5-( ⁇ 2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl ⁇ oxy) -2-methylphenyl] -1,
• Compound A and salts thereof have a strong kinase inhibitory activity and are known to be useful for the prevention / treatment of cancer, the prevention / treatment of diabetic retinopathy, etc. (Patent Document 1).
• Patent Document 1 since compound A and its salts are sparingly soluble in water, there has been no specific study of aqueous liquids, particularly the stability in aqueous liquids.
• the present inventors have examined an aqueous solution containing Compound A or a salt thereof, and found that there is a problem that the content of Compound A or a salt thereof decreases with time in the aqueous solution.
• the object of the present invention is to solve the problem which is such a new finding, and the stability of the compound A and its salt in the aqueous solution is improved (in other words, the content of the compound A and its salt in the aqueous solution is improved). It is to provide an aqueous solution in which a decrease is suppressed.
• Another object of the present invention is to provide a method for stabilizing Compound A and its salt in an aqueous liquid, and a stabilizer for Compound A and its salt in an aqueous liquid.
• the present inventors have found that compound A and its salt in an aqueous liquid preparation are stabilized by adding ethylenediaminetetraacetic acid or its salt or its hydrate ( In other words, it was found that the decrease in the content of Compound A and its salt in the aqueous liquid was suppressed). Further, the present inventors have found that compound A and its salt are further stabilized in an oil-in-water emulsion to which ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof is added. Based on the above findings, the inventors of the present invention made further studies and completed the present invention.
• the present invention provides the following.
• [1] N- [5-( ⁇ 2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl ⁇ oxy) -2-methylphenyl] -1,3-dimethyl-1H -An aqueous liquid preparation containing pyrazole-5-carboxamide or a salt thereof and ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof (also referred to herein as the aqueous liquid preparation of the present invention).
• the agent according to the above [1] which is an oil-in-water emulsion (also referred to herein as the oil-in-water emulsion of the present invention).
• an ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof to an aqueous liquid (preferably an oil-in-water emulsion) containing Compound A or a salt thereof, Compound A in the aqueous liquid and An aqueous liquid with improved stability of the salt can be provided.
• an aqueous liquid preferably an oil-in-water emulsion
• the “aqueous liquid” is a liquid containing water, and examples thereof include water and an oil-in-water emulsion.
• the aqueous liquid is a liquid in which substances other than water are usually 50% by mass or less, preferably 25% by mass or less, and the aqueous phase is a continuous phase.
• the “aqueous liquid agent” refers to an aqueous liquid which is an embodiment of a pharmaceutical preparation containing Compound A or a salt thereof, and refers to an aqueous solution, a suspension, an emulsion (eg, oil-in-water emulsion) and the like.
• the aqueous liquid preparation of the present invention contains Compound A or a salt thereof.
• the content of Compound A or a salt thereof in the aqueous liquid preparation of the present invention is usually 0.002 to 2 w / v%, preferably 0.005 to 0.2 w / v%, more preferably 0, relative to the total amount of the aqueous liquid preparation. 0.005 to 0.1 w / v%.
• the salt of Compound A includes pharmaceutically acceptable salts, for example, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
• the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
• salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene And salts with sulfonic acid, p-toluenesulfonic acid and the like.
• salts with basic amino acids include salts with arginine, lysine, ornithine and the like
• salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.
• the aqueous liquid preparation of the present invention contains ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof.
• examples of the salt of ethylenediaminetetraacetic acid include sodium salt, potassium salt, calcium salt, and magnesium salt, and sodium salt is preferable.
• ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof includes, for example, disodium ethylenediaminetetraacetate, disodium ethylenediaminetetraacetate dihydrate, and disodium ethylenediaminetetraacetate is preferred. .
• the content of ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof in the aqueous solution of the present invention is usually 0.001 to 0.2 w / v%, preferably 0.005 to 0.05 w, based on the total amount of the aqueous solution. / V%, more preferably 0.01 to 0.03 w / v%, still more preferably 0.01 to 0.02 w / v%.
• the aqueous liquid preparation of the present invention is preferably an oil-in-water emulsion since the stabilizing effect of compounding ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof on compound A and its salt is more remarkable in the emulsion.
• the oil component in the oil-in-water emulsion of the present invention include castor oil, rapeseed oil, cottonseed oil, soybean oil, corn oil, olive oil, liquid paraffin, medium chain fatty acid triglyceride, fatty acid (eg, ricinoleic acid, oleic acid), fat Group alcohol (eg, oleyl alcohol), and castor oil is preferred.
• the oil-in-water emulsion of the present invention containing castor oil as an oil component is excellent in that it suppresses a decrease in the daily content of Compound A and its salt in an aqueous solution. Since compound A and its salt exhibit excellent solubility, it is preferable to use castor oil as the oil component.
• the content of the oil component in the oil-in-water emulsion of the present invention is usually 0.1 to 50% w / v%, preferably 0.5 to 20% w / v%, more preferably based on the total amount of the aqueous liquid preparation. 1 to 10% w / v%.
• the oil-in-water emulsion of the present invention usually contains an emulsifier.
• a surfactant for example, a nonionic surfactant having a surface active ability can be blended.
• nonionic surfactants include polyoxyethylene hydrogenated castor oils, polyoxyethylene sorbitan fatty acid esters (eg, polyoxyethylene sorbitan monooleates, polyoxyethylene sorbitan monolaurates, polyoxyethylene sorbitan mono Palmitates, polyoxyethylene sorbitan monostearates, etc.).
• polysorbate 80 is mentioned as an example of polyoxyethylene sorbitan monooleates.
• polyoxyethylene sorbitan monooleates are preferable.
• the content of the emulsifier in the oil-in-water emulsion of the present invention is usually 20 to 200 w / w%, preferably 30 to 150 w / w%, more preferably 60 to 120 w / w% based on the oil component.
• a buffering agent may be blended in the oil-in-water emulsion of the present invention.
• buffers include acetates such as sodium acetate, phosphates such as monosodium dihydrogen phosphate, disodium monohydrogen phosphate, dipotassium dihydrogen phosphate, dipotassium monohydrogen phosphate, and epsilon aminocaproic acid.
• Amino acid salts such as sodium glutamate, boric acid and its salts, citric acid and its salts, etc., and sodium acetate is preferred.
• the content of the buffer in the oil-in-water emulsion of the present invention is usually from 0.01 to 1 w / v%, preferably from 0.02 to 0.5 w / v%, more preferably from 0. 05-0.2 w / v%.
• An isotonic agent can be blended in the oil-in-water emulsion of the present invention.
• isotonic agents include sodium chloride, glycerin (eg, concentrated glycerin), propylene glycol, glucose, mannitol, sorbitol, and the like, and glycerin (eg, concentrated glycerin) is preferred.
• the content of the isotonic agent in the oil-in-water emulsion of the present invention is such that the osmotic pressure of the aqueous liquid is usually 200 to 400 mOsm, preferably 250 to 350 mOsm, more preferably 270 to 330 mOsm.
• a water-soluble polymer can be blended in order to improve the emulsion stability.
• the water-soluble polymer include povidone (polyvinyl pyrrolidone), polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof.
• a preservative can be added to the oil-in-water emulsion of the present invention.
• preservatives include quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride, cationic compounds such as chlorhexidine gluconate, paraoxybenzoates such as methyl paraoxybenzoate and propyl paraoxybenzoate, chlorobutanol, Examples include alcohol compounds such as benzyl alcohol, sodium dehydroacetate, thimerosal, and sorbic acid.
• various additives such as a stabilizer, an antioxidant, a pH adjuster, and a thickener can be blended.
• antioxidant examples include ascorbic acid and its salt, tocopherol, sodium thiosulfate, sodium bisulfite, pyruvic acid and its salt, and the like.
• pH adjuster examples include hydrochloric acid, phosphoric acid, acetic acid, sulfuric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, aqueous ammonia, and the like.
• the pH of the oil-in-water emulsion of the present invention is preferably 3 to 8, and more preferably 4 to 6.
• the median diameter of the oil droplets of the oil-in-water emulsion of the present invention is preferably 0.0001 to 5 ⁇ m, more preferably 0.001 to 1 ⁇ m, and particularly preferably 0.01 to 1 ⁇ m.
• the median diameter can be measured using a particle size distribution measuring apparatus.
• the oil-in-water emulsion of the present invention can be prepared using a known technique.
• the oil component in which Compound A or a salt thereof is dissolved and water in which ethylenediaminetetraacetic acid or a salt or hydrate thereof is dissolved are emulsified using an emulsifier to prepare the oil-in-water emulsion of the present invention.
• an emulsifier; ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof; and, if necessary, the above additives are added, and an oil in which compound A or a salt thereof is dissolved is added to form an emulsion.
• known means such as a homomixer, a homogenizer, a microfluidizer, and a high-pressure homogenizer can be used.
• the aqueous liquid preparation of the present invention is an aqueous solution containing the compound A or a salt thereof (hereinafter also referred to as the aqueous solution preparation of the present invention).
• buffers aqueous solution containing the compound A or a salt thereof
• pH adjusters aqueous solution preparation of the present invention
• surfactants that are usually used
• Various additives such as these may be added as appropriate.
• the buffer, tonicity agent, and pH adjuster are the same as those exemplified for the oil-in-water emulsion.
• the surfactant include nonionic surfactants.
• nonionic surfactants include polyoxyethylene hydrogenated castor oils or polyoxyethylene sorbitan fatty acid esters, preferably polyoxyethylene sorbitan monooleates (eg, polysorbate 80), polyoxyethylene sorbitan monolaurates , Polyoxyethylene sorbitan monopalmitates, polyoxyethylene sorbitan monostearates and the like.
• the content of the buffer in the aqueous solution of the present invention is usually from 0.01 to 1 w / v%, preferably from 0.02 to 0.5 w / v%, more preferably from 0.05 to 1.0%, based on the total amount of the aqueous solution. 0.2 w / v%.
• the content of the isotonic agent in the aqueous solution of the present invention is such that the osmotic pressure of the aqueous solution is usually 200 to 400 mOsm, preferably 250 to 350 mOsm, more preferably 270 to 330 mOsm.
• the content of the surfactant in the aqueous solution of the present invention is usually 0.05 to 10 w / v% with respect to the total amount of the aqueous solution.
• the pH of the aqueous solution of the present invention is preferably 3 to 8, and more preferably 4 to 6.
• the aqueous solution of the present invention can be prepared by dissolving compound A or a salt thereof; ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof; and, if necessary, the above-described additives in water using a known technique.
• the suspending agent an additive according to the above aqueous solution and the blending amount of each component are applied.
• the aqueous liquid preparation of the present invention can be used for mammals (humans, dogs, rabbits, cows, horses, monkeys, cats, sheep, etc.) as a prophylactic / therapeutic agent for eye diseases such as diabetic retinopathy. it can.
• the aqueous liquid preparation of the present invention can be made into a dosage form of an aqueous liquid preparation for oral administration or parenteral administration.
• Compound A or a salt thereof is used for an eye disease such as diabetic retinopathy, an eye drop is preferable. .
• the dosage of the aqueous liquid preparation of the present invention varies depending on the type of disease, symptoms, patient age, body weight, etc.
• Compound A or a salt thereof per eye per patient As an ophthalmic solution containing about 0.002 to 2 w / v%, it is desirable to administer 1 to 2 drops at a time, about 1 to 4 times a day, depending on the symptoms.
• the present invention is also a method for stabilizing Compound A and a salt thereof in an aqueous liquid, wherein Compound A or a salt thereof, and ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof are added to the aqueous liquid. It is related with the method characterized.
• the blending order is not particularly limited. For example, compound A or a salt thereof is added to an aqueous liquid in which ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof is previously mixed; or ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof and compound A or The salt can be blended into the aqueous liquid at the same time.
• aqueous liquid is an oil-in-water emulsion
• compound A or a salt thereof is dissolved in the oil and blended.
• the preparation in the method of the present invention is performed in the same manner as the preparation of the aqueous liquid preparation.
• the blending amount of ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof conforms to the amount described in the aqueous liquid preparation.
• a step of confirming stabilization for example, a step of measuring the content of Compound A or a salt thereof in an aqueous liquid, a step of measuring a residual ratio of Compound A or a salt thereof in the aqueous liquid, A step of measuring the half-life of compound A or a salt thereof, and the like.
• the step of measuring the content, the step of measuring the residual rate, and the step of measuring the half-life can be performed, for example, according to Test Example 1 described later.
• the present invention further relates to a stabilizer for compound A and its salt in an aqueous liquid containing ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof.
• the stabilizer of the present invention includes at least ethylenediaminetetraacetic acid or a salt thereof or a hydrate thereof, and further includes various additives such as a buffer, an isotonic agent, a pH adjuster, and a surfactant. May be.
• the stabilizer can be used in the same manner as in the preparation of an aqueous solution.
• this invention relates to the stabilizer of the compound A and its salt in aqueous liquid which combines ethylenediaminetetraacetic acid or its salt, or its hydrate, and a castor oil.
• a stabilizing effect by castor oil in the oil phase of the oil-in-water emulsion is exhibited.
• Examples 1 and 2 According to the formulation shown in Table 1, compound A, polysorbate 80, concentrated glycerin, sodium acetate and sodium edetate were added to and dissolved in purified water, and the pH of the aqueous solutions of Examples 1 and 2 was adjusted to 5.5 with hydrochloric acid. A liquid (compound A-containing aqueous solution) was obtained.
• Examples 3 and 4 According to the formulation shown in Table 1, polysorbate 80, concentrated glycerin, sodium acetate and sodium edetate were added to and dissolved in purified water to obtain an aqueous phase. Separately, according to the formulation shown in Table 1, compound A was added to castor oil and dissolved to obtain an oil phase. The aqueous phase is T.W. K. While stirring with Robomix (manufactured by Primics), the oil phase was added to obtain a crude emulsion.
• the crude emulsion was microparticulated with a fill mix (manufactured by PRIMIX), and the pH was adjusted to 5.5 with hydrochloric acid to obtain aqueous solutions (compound A-containing oil-in-water emulsions) of Examples 3 and 4.
• Test Example 1 Stability test The aqueous solutions obtained in Examples 1 to 4 and Comparative Examples 1 to 4 were filled in glass ampoules, respectively, and stored at 60 ° C for 5, 7, and 14 days. The content of Compound A in each specimen after storage was measured by the following method.
• HPLC measurement condition detector ultraviolet absorptiometer (measurement wavelength 230 nm)
• Flow rate Adjusted so that the retention time of Compound A is about 8 minutes.
• An aqueous liquid preparation (for example, eye drops) containing Compound A or a salt thereof of the present invention has improved stability of Compound A or a salt thereof in the aqueous liquid preparation and is useful as a medicine.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Ophthalmology & Optometry (AREA)
• Engineering & Computer Science (AREA)
• Dispersion Chemistry (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=56107476

Family Applications (1)

Country Status (4)

Citations (7)

Family Cites Families (1)

• 2015
  • 2015-12-10 EP EP15868436.5A patent/EP3231427A4/de not_active Withdrawn
  • 2015-12-10 US US15/534,915 patent/US20180028667A1/en not_active Abandoned
  • 2015-12-10 JP JP2016563728A patent/JPWO2016093299A1/ja active Pending
  • 2015-12-10 WO PCT/JP2015/084618 patent/WO2016093299A1/ja active Application Filing

Patent Citations (7)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events